Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes

Scripps Genomic Medicine and Scripps Translational Science Institute, La Jolla, California, United States of America.
PLoS Genetics (Impact Factor: 7.53). 06/2011; 7(6):e1002134. DOI: 10.1371/journal.pgen.1002134
Source: PubMed


Author Summary
Bipolar disorder (BD) is a highly heritable disease that has been difficult to characterize genetically. We have genotyped 1,190 BD cases and 401 controls to find regions of the genome associated with BD. After combining these data with previously existing genotyped samples, we did not find any genome-wide significant associations. However, when we used an additional study to prioritize loci for replication and meta-analysis purposes, we found that we were more likely to see an association in our sample with variants for which we had the highest power. We quantified this effect using logistic regression and saw a strong association between power to detect an effect based on an initial study's results and replication P-value in a second study (P = 1.5×10−7), supporting the presence of shared genetic risk factors across the studies. Moreover, this association was stronger when we restricted analysis to SNPs near coding regions, and it was further enriched when SNPs had the same direction of effect in both studies. This result supports the presence of genetic factors underlying BD near exons whose collective effect results in a detectable signal and provides a framework for assessing the potential for replication when combining results from multiple studies.

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Available from: Howard Edenberg
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    • "One caveat to the study of SNPs within non-genic regions is that, while it is known that common SNPs explain a substantial portion of heritability, not all SNPs contribute equally to the heritability of a trait. SNPs in genes explain the most heritability, while those near genes (or in areas regulating them) explain some, and those in non-genic regions (SNP deserts) explain little of the heritability (Smith et al., 2011; Yang et al., 2011; Schork et al., 2013). Despite this, it remains possible that SNPs located outside of coding regions represent a new class of regulatory SNPs that make an important contribution toward explaining heritability. "
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    • "In the case of positive associations with different SNPs in the same gene, we cannot exclude the replica value because haplotype-specific functional variations have not been analysed. A recent GWAS study on bipolar patients showed that there is likely common genetic variation associated with the disorder near exons (±10 kb) that could be identified in larger studies and also provided a framework for assessing the potential for replication when combining results from multiple studies [41]. "
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